Alzheimer's disease (AD) is a chronic neurodegenerative disorder that typically manifests clinically in the elderly. Interestingly, a variety of postmortem evidence suggests that the pathological hallmarks of AD, and by inference the disease itself, begin to occur early in an individual's life. This has led to an emerging view of AD whereby a set of disparate mechanistic triggers over a life-time converge upon shared biochemical pathways to elicit a phenotypically similar clinical syndrome and neuropathological state. This convergent pathophysiological hypothesis asserts that specific downstream biochemical pathways mediate the synaptic loss, cellular injury, and death observed in AD. Furthermore, many of these pathophysiological changes will be manifest in peripheral systems, which share these signaling pathways. We hypothesize that the hematopoietic system shares many cellular signaling pathways with the nervous system and is affected by many of the same pathophysiological changes that characterize AD. Specifically, we propose that peripheral leukocytes are affected by AD pathogenic processes, which will be reflected in alterations in protein levels and functions. As such, these changes will serve as important biomarkers for AD diagnosis and progression and will provide valuable insights into its pathophysiology and potential therapeutics. We propose to identify and collect serial clinical measurements and biological samples from three cohorts: subjects at high risk for developing mild-cognitive impairment (MCI)/AD (>75 years old with a first degree relative diagnosed with AD); age-and gender-matched subjects at low risk; and newly diagnosed, drug-naive subjects with MCI/AD. In Specific Aim 1 we will undertake an extensive clinical and biomolecular examination of all high risk subjects that progress to a diagnosis of MCI/AD compared to an appropriately matched subset of low risk subjects without MCI/AD to discover and validate a potential biomarker profile of disease. In Specific Aim 2 we will test the specificity and sensitivity of this profile in a second subset of the low risk cohort without MCI/AD and early, drug-naive MCI/AD subjects. We hypothesize that the clinical-biomolecular profile identified in these studies will be important to our understanding of disease diagnosis, pathogenesis, and therapy in AD. With the aging of America's baby boomers the need to fully understand the pathogenesis of this disease and to design molecular diagnostics and improved pharmacotherapies is vitally important to our nation and our health care systems. As such, it is necessary to develop robust, specific, and sensitive biomarkers of early AD, which would greatly facilitate the diagnosis and treatment of this disease. PUBLIC HEALTH RELEVANCE: We hypothesize that the clinical-biomolecular profile identified in these studies will be important to our understanding of disease diagnosis, pathogenesis, and therapy in AD. With the aging of America's baby boomers the need to fully understand the pathogenesis of this disease and to design molecular diagnostics and improved pharmacotherapies is vitally important to our nation and our health care systems. As such, it is necessary to develop robust, specific, and sensitive biomarkers of early AD, which would greatly facilitate the diagnosis and treatment of this disease.